Over the nearly 20 year span of this PPG, we have demonstrated that multiple genetic variants lead to varying Immune reactions defined by antibody expression, and are related to different clinical phenotypes. Examples include the relationship between functional variants in both NFKB1 and TNFSF15 and high-level antibody responses to single and/or multiple anti-microbial antigens and, therefore, aggressive IBD. The continuing focus for the current PPG is to understand the relationship between the innate and adaptive immune response and the effect on disease severity. We hypothesize that patients who lack antibody responses to bacterial antigens and who have mild, non-progressive disease, are likely to 'carry' genetic variants associated with mildly defective innate responses and that exposure to commensal bacteria in these individuals results in a somewhat decreased protection from bacterial invasion. This decreased protection permits a slightly increased bacterial exposure, yielding little to no increased adaptive immune response and hence a milder clinical phenotype with non-progressing disease. In contrast, patients who express high level antibody response to single or multiple microbial antigens may carry genetic variants associated with defects in the innate immune system that generate a severely modified innate immune response. Therefore, in these patients, exposure to commensal bacteria and/or concomitant mucosal injury would lead to markedly decreased protection and greatly increased bacterial exposure. Depending on the presence of any additional genetic defects, causing either a defective regulatory cell population, a potent effector T-cell population and/or abnormal cytokine regulation, these conditions would lead to a markedly increased Th1 or Th17 adaptive immune response, associated with severe, rapidly progressive mucosal inflammation. The advances in the field, focused by the multiple contributions from this PPG form the foundation of this paradigm, which should allow us to address underlying genetic variants (Project 1) and immunophysiologic abnormalities in innate immune (Projects 2 & 5), Th1 and Th17 effector (Projects 2 & 4), and/or regulatory cell populations (Project 3) or T cell co-stimulatory pathways (Projects 1, 2 & 4), associated with these adaptive immune responses in both mouse and man. It is upon this hypothesis and paradigm that this fifth competing continuation of our PPG is based. The central theme is to utilize newly discovered disease related genetic variation to understand the in vitro (human) and in vivo (mouse) mechanisms involved in the innate/adaptive immune interface associated with severe mucosal inflammation, and severity of IBD. PUBLIC HEALTH RELEVANCE: Inflammatory bowel diseases affect more than one million Americans and the incidence is rising. The work described in the program project proposal will further understanding of the causes of these diseases and aid in the development of patient-specific therapies. TABLE OF CONTENTS Overall Description 2